Despite major efforts, pancreatic cancer (PaC) still carries a poor prognosis [1]. While PaC is only the 10th most common cancer, it is the 4th leading cause of cancer death in the USA [2-4]. In fact, the 5-year survival is <5%, the lowest of all malignancies [2-3]. However, recent data have shown that the outcome could be dramatically improved by early detection when the cancer is still predominantly at stage I, as illustrated by a 5-year survival of 30-60% (≦20 mm sized tumour) and even >75% (≦10 mm sized tumour) after early PaC resection [2-4].
PaC is characterized by a rapid tumour progression, early metastasization, and unresponsiveness to most conventional therapies [1, 5]. The poor prognosis is mainly due to the lack of effective early diagnostics combined with that disease-specific clinical symptoms occur late in the course of the disease. At the time of diagnosis, the tumour has often reached a size of 30-40 mm and a majority of all patients (52%) already have metastases, 26% locally advanced cancer, and only 7% have tumours confined to the pancreas [2, 4]. At this time, about 15% of the patients are still operable, but their median survival is only 20 months.
A variety of non-invasive methodologies, including (endoscopic) ultrasound, computed tomography, and/or endoscopic retrograde cholangio-pancreatography, are used for PaC diagnostics [1-2, 6]. Albeit powerful, these methods are not specific for PaC and not designed for early detection when the tumour is still small and potentially curable. The situation is further complicated by the fact that PaC is difficult to differentiate from benign conditions, such as chronic pancreatitis, using currently available diagnostic tools [2]. Hence, the use of biomarkers for specific and early detection of PaC would be of invaluable clinical benefit.
In spite of major efforts, molecular fingerprints associated with PaC from in particular, crude, non-fractionated serum and plasma, remains to be deciphered [2, 7-9]. Among the number of mainly single biomarkers that have been outlined so far, including e.g. CRP, CA 242, GDF-15, haptoglobin, M2-pyruvate kinase, serum amyloid A, IGFBP-1, none have proven to be clinically superior to CA 19-9 [2, 8-10]. Still, the use of CA 19-9 is significantly hampered by the fact that it has been found to i) be elevated in both non-malignant conditions (e.g. pancreatitis and acute cholangitis) and other gastro-intestinal cancers (e.g. gastric cancer and colorectal cancer), ii) lack sensitivity for early PaC, and iii) be absent in about 10% of the population [2, 8-10]. When screening for PaC, CA 19-9 has only yielded medium sensitivity (ranging from 69% to 98%) and specificity (46% to 98%) [2, 9-11].
Against this background, the inventors developed a proteomic approach to prognostic diagnosis of cancer in WO 2008/117067 whereby the first sets of serum biomarkers for detection of pancreatic cancer and for predicting survival were identified.